The art knows of using magnetically-driven stir bars, or impellers, within a formulation bottle for mixing the fluid contents of the container. The impeller is manually emplaced to be centrally-located over the bottom of the formulation bottle such that an external magnetic drive will be able to rotate the impeller within the formulation bottle. The placement of the impeller must ensure that the impeller is properly located over the magnetic drive as positioning the impeller off-center of the axis of rotation of the magnetic drive will cause the impeller to spin out of position, requiring the process to be shut down while the impeller is repositioned.
The current method of adding the stir bar to the fluid can cause numerous problems. First, the stir bar must be dropped through an open port on the top of the formulation bottle. Having an opening on the top of the formulation bottle is highly undesirable since it contains a radioactive solution. Once the stir bar is deposited into the formulation bottle it must be perfectly centered inside the formulation bottle, and thus centered on the magnetic drive underneath the formulation bottle. If the stir bar is not perfectly centered it will be magnetically driven off path (out of the center) and not rotate correctly to produce the vortex needed for the homogeneous mixture. If this happens it is common to try to adjust the stir bar inside the bottle with a long needle, or by tilting the bottle to try to center the stir bar.
Using a long needle is undesirable due to the radiation exposure associated with handling a long needle above the bottle. Adding additional contact materials into the bottle is also undesirable since the solution is ultimately used for human injection. Tilting the bottle to try to center the stir bar is also undesirable since the radiation exposure to the operator will be greater, and also because the bottle is usually inside of high Z material for radiation shielding and not easily accessible. Numerous formulation bottles have been cracked or even broken due to this type of manual manipulation to resolve this type of issue. Sterility, or at a minimum sanitization, of the stir bar and/or method of centering the stir bar is also a challenge to the current method. It is also possible that the stir bar is centered in the formulation bottle, but the magnetic drive is dialed up too quickly, this commonly causes the stir bar to jump out of the center location and will require the stir bar to be re-centered. There is quite a bit of technique and experience required to deposit the stir bar correctly and to increase the magnetic drive enough to produce the vortex required to produce a homogeneous mixture, without increasing the magnetic drive too high causing the stir bar to jump out of center.
Another problem associated with the current method is dropping the stir bar into the solution causing a crack or even break in the formulation bottle. A final issue related to the current method is that the formulation bottle is located inside of a heavy high Z material for shielding the operator from the radioactive field, because of this the visual confirmation of a stir bar being correctly dropped, or even correctly working, can be extremely challenging. It is possible to position mirrors above the bottle to see the vortex from a correctly positioned and working stir bar, but this can also be challenging since re-positioning or re-working an added stir bar would be observed as a mirrored image, and thus not necessarily advantageous to the operator.
Another issue associated to the currently used formulation bottle is that the fluid needs to be extracted from the lowest position of the bottle to get as much fluid as possible. This is currently accomplished by placing a needle, or in some cases a tube, through a hole or septum at the top of the bottle with the tip of the needle, or end of the tube, being positioned in the bottom of the bottle. This can cause interference with the stir bar mentioned above, or can cause several other undesirable issues. Another issue related to this current method is associated with the radioactive nature of the material inside the bottle, and the extremity exposure to the operator positioning the needle and/or tubing. If there are any blockages in the fluid path, or repositioning is required for any reason, the operator is exposed to this radioactive field. There are sterility, or at a minimum of sanitization, issues associated to the different fluid path materials used for this method. If a needle tip, or the end of a tube, are not positioned exactly right there will be a reduced volume extracted from the formulation bottle.
Thus, the current process of manually adding an extraction needle or tube include, setting the needle or tube in the lowest position, where operator to operator variability of placing the extraction path can vary the results from batch to batch. Additionally, adding more fluid path or handling devices into the container can cause sterility or additive bio-burden associated with the multiple fluid path components or devices. There is again the risk of operator exposure to the product fluid while trying to position or re-position a tube to the lowest portion of the container, which are made more difficult by the container being located within an outer shielding container.
There have been numerous failed formulation lots due to these issues; in addition, there have been diminished production volumes because of the limits of the current method and equipment.